CN113429379A - LH-1801 intermediate and preparation method and application thereof - Google Patents
LH-1801 intermediate and preparation method and application thereof Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- 150000001875 compounds Chemical class 0.000 claims abstract description 55
- 238000006243 chemical reaction Methods 0.000 claims abstract description 37
- ACHSDAONLOEIFS-UHFFFAOYSA-N [2-bromo-5-chloro-4-[(5-ethylthiophen-2-yl)methyl]phenyl]methanol Chemical group CCC1=CC=C(CC2=CC(Br)=C(CO)C=C2Cl)S1 ACHSDAONLOEIFS-UHFFFAOYSA-N 0.000 claims abstract description 8
- 238000004519 manufacturing process Methods 0.000 claims abstract description 7
- -1 2- (5-bromo-2-chloro-4- (methoxymethyl) benzyl) -5-ethylthiophene Chemical compound 0.000 claims description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- 239000003054 catalyst Substances 0.000 claims description 14
- 230000035484 reaction time Effects 0.000 claims description 12
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 11
- 238000010438 heat treatment Methods 0.000 claims description 11
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 10
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 claims description 10
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 10
- UOXJNGFFPMOZDM-UHFFFAOYSA-N 2-[di(propan-2-yl)amino]ethylsulfanyl-methylphosphinic acid Chemical compound CC(C)N(C(C)C)CCSP(C)(O)=O UOXJNGFFPMOZDM-UHFFFAOYSA-N 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 6
- KWEKXPWNFQBJAY-UHFFFAOYSA-N (dimethyl-$l^{3}-silanyl)oxy-dimethylsilicon Chemical compound C[Si](C)O[Si](C)C KWEKXPWNFQBJAY-UHFFFAOYSA-N 0.000 claims description 5
- JCCCMAAJYSNBPR-UHFFFAOYSA-N 2-ethylthiophene Chemical compound CCC1=CC=CS1 JCCCMAAJYSNBPR-UHFFFAOYSA-N 0.000 claims description 5
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 claims description 4
- SFHYNDMGZXWXBU-LIMNOBDPSA-N 6-amino-2-[[(e)-(3-formylphenyl)methylideneamino]carbamoylamino]-1,3-dioxobenzo[de]isoquinoline-5,8-disulfonic acid Chemical compound O=C1C(C2=3)=CC(S(O)(=O)=O)=CC=3C(N)=C(S(O)(=O)=O)C=C2C(=O)N1NC(=O)N\N=C\C1=CC=CC(C=O)=C1 SFHYNDMGZXWXBU-LIMNOBDPSA-N 0.000 claims description 4
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
- HTFNVAVTYILUCF-UHFFFAOYSA-N 2-[2-ethoxy-4-[4-(4-methylpiperazin-1-yl)piperidine-1-carbonyl]anilino]-5-methyl-11-methylsulfonylpyrimido[4,5-b][1,4]benzodiazepin-6-one Chemical compound CCOc1cc(ccc1Nc1ncc2N(C)C(=O)c3ccccc3N(c2n1)S(C)(=O)=O)C(=O)N1CCC(CC1)N1CCN(C)CC1 HTFNVAVTYILUCF-UHFFFAOYSA-N 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 abstract description 12
- 238000003786 synthesis reaction Methods 0.000 abstract description 12
- 238000006757 chemical reactions by type Methods 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract description 2
- 230000002194 synthesizing effect Effects 0.000 abstract description 2
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 17
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 10
- 238000005160 1H NMR spectroscopy Methods 0.000 description 9
- 238000001035 drying Methods 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 239000007810 chemical reaction solvent Substances 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 238000010172 mouse model Methods 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 238000005303 weighing Methods 0.000 description 4
- WZZDFLXTHBVRGY-UHFFFAOYSA-N 5-bromo-2-chloro-4-methylbenzoic acid Chemical compound CC1=CC(Cl)=C(C(O)=O)C=C1Br WZZDFLXTHBVRGY-UHFFFAOYSA-N 0.000 description 3
- 108091006269 SLC5A2 Proteins 0.000 description 3
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 3
- IYZCGVHGVXENKL-UHFFFAOYSA-N methyl 5-bromo-2-chloro-4-methylbenzoate Chemical compound COC(=O)C1=CC(Br)=C(C)C=C1Cl IYZCGVHGVXENKL-UHFFFAOYSA-N 0.000 description 3
- AXUSQXOXCJCPAC-UHFFFAOYSA-N methyl 5-bromo-4-(bromomethyl)-2-chlorobenzoate Chemical compound BrC=1C(=CC(=C(C(=O)OC)C=1)Cl)CBr AXUSQXOXCJCPAC-UHFFFAOYSA-N 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- 102000058081 Sodium-Glucose Transporter 2 Human genes 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 230000003285 pharmacodynamic effect Effects 0.000 description 2
- 230000002269 spontaneous effect Effects 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- MYJUBDJLKREUGU-UHFFFAOYSA-N 2-chloro-4-methylbenzoic acid Chemical compound CC1=CC=C(C(O)=O)C(Cl)=C1 MYJUBDJLKREUGU-UHFFFAOYSA-N 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- JVHXJTBJCFBINQ-ADAARDCZSA-N Dapagliflozin Chemical compound C1=CC(OCC)=CC=C1CC1=CC([C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)=CC=C1Cl JVHXJTBJCFBINQ-ADAARDCZSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 241000124033 Salix Species 0.000 description 1
- 230000003178 anti-diabetic effect Effects 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 229960003834 dapagliflozin Drugs 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 1
- 201000001421 hyperglycemia Diseases 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 239000003538 oral antidiabetic agent Substances 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 238000005556 structure-activity relationship Methods 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 230000009897 systematic effect Effects 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
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-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
- C07D333/16—Radicals substituted by singly bound hetero atoms other than halogen by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/10—Spiro-condensed systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention discloses an LH-1801 intermediate, a preparation method and an application thereof, wherein the intermediate is (2-bromo-5-chloro-4- ((5-ethylthiophene-2-yl) methyl) phenyl) methanol, and the structural formula of the intermediate is shown as follows. The invention provides a brand-new LH-1801 intermediate and new compounds A8 and A9 for synthesizing the intermediate, and the LH-1801 synthesized by the intermediate can reduce the production risk and improve the product quality. In addition, the intermediate is synthesized by adopting a brand new intermediate compound and a synthesis route, so that the reaction risk is effectively reduced, the reaction type is simple, no dangerous reaction exists, the condition is mild, and the raw materials are easy to obtain.
Description
Technical Field
The invention belongs to the technical field of intermediate compounds, and particularly relates to an LH-1801 intermediate, and a preparation method and application thereof.
Background
LH-1801, of the formula:
preclinical research of the system shows that LH-1801 has excellent SGLT2 inhibition activity, can improve hyperglycemia of spontaneous type 2 diabetes model mice and STZ-induced type 1 diabetes model mice, and has the characteristics of low effective dose and obvious hypoglycemic effect. The drug effect of LH-1801 in a plurality of animal models is superior to that of the marketed drug dapagliflozin, has good pharmacokinetic characteristics and safety in rats and dogs, is a safe, effective and quality-controllable antidiabetic clinical candidate drug, and has good patent drug prospect. Clinical trials of the product have approved to provide safe and effective potential treatment options for patients with type 2 diabetes and type 1 diabetes. The salix red subject group designs and synthesizes a SGLT2 small molecule inhibitor with a novel structure aiming at the association-dissociation kinetic characteristics of a sugar recognition site of an SGLT2 transporter, and develops the structure-activity relationship research of a system; lijia topic group carries out systematic in vitro and in vivo activity screening and pharmacodynamic evaluation on the inhibitor, and 7 animal model pharmacodynamic evaluations are carried out by adopting spontaneous type 2 diabetes model mice, STZ induced type 1 diabetes model mice and the like. A new class-1 oral hypoglycemic drug LH-1801 which is independently developed by combining Shanghai drug research institute of Chinese academy of sciences and Liuhong drug research institute is obtained in 11-25 months of 2020 and informed about clinical tests issued by the State drug administration, and the clinical tests are agreed to be carried out.
At present, an intermediate LH-1801 which can reduce the production risk and improve the product quality is urgently needed to be provided.
Disclosure of Invention
The purpose of the invention is as follows: aiming at the problems in the prior art, the invention provides an LH-1801 intermediate, a preparation method and application thereof, and the LH-1801 is synthesized by using the intermediate, so that the production risk is reduced, and the product quality can be improved.
The technical scheme is as follows: in order to achieve the purpose of the invention, the technical scheme adopted by the invention is as follows:
an LH-1801 intermediate which is (2-bromo-5-chloro-4- ((5-ethylthiophen-2-yl) methyl) phenyl) methanol having the formula:
a compound useful for preparing said LH-1801 intermediate, said compound being 2- (5-bromo-2-chloro-4- (methoxymethyl) benzyl) -5-ethylthiophene, having the formula shown in A8 below:
a compound useful for preparing said LH-1801 intermediate, said compound being 2- (5-bromo-4- (bromomethyl) -2-chlorobenzyl) -5-ethylthiophene, having the formula shown in a9 below:
the preparation method of the LH-1801 intermediate, the compound A8 or the compound A9 comprises the following steps:
(1) reacting the compound A4 with sodium methoxide under heating to obtain a compound A5;
(2) reacting the compound A5 with thionyl chloride to obtain a compound A6;
(3) reacting the compound A6 with 2-ethyl thiophene under the condition of a catalyst to obtain a reaction solution containing a compound A7;
(4) adding a catalyst and 1,1,3, 3-tetramethyldisiloxane into a reaction solution containing a compound A7, and heating for reaction to obtain a compound A8;
(5) reacting the compound A8 with boron tribromide to obtain a compound A9;
(6) and heating the compound A9 under the alkali condition for reaction to obtain a final target product compound A10.
Preferably, in step (1), compound a4 is prepared mainly by the following method:
(1) reacting the compound A1 with bromine under the condition of a catalyst to obtain a compound A2;
(2) reacting the compound A2 with methanol under heating to obtain a compound A3;
(3) and heating and reacting the compound A3 with azodiisobutyronitrile and N-bromosuccinimide to obtain a compound A4.
Preferably, in the step (1), the reaction temperature is 55-75 ℃, and the reaction time is 6-8 hours; the reaction solvent is selected from methanol, the volume ratio of the mass of A4 to the methanol is 1: 5-1: 20, and the molar ratio of A4 to sodium methoxide is 1: 1.5-1: 5;
preferably, in the step (2), the reaction temperature is 55-75 ℃, and the reaction time is 6-8 hours; the molar ratio of the A5 to the thionyl chloride is 1: 1-1: 4, the reaction solvent is a mixed solvent of DMF and toluene, the molar ratio of the A5 to the DMF is 1: 0.005-1: 0.2, and the ratio of the mass of the A5 to the volume of the toluene is 1: 3-1: 12.
Preferably, in the step (3), the catalyst is selected from anhydrous aluminum chloride, the reaction temperature is 40-60 ℃, and the reaction time is 1.5-2.5 hours; the molar ratio of the A6 to the catalyst is 1: 1-1: 2.5, the molar ratio of the A6 to the 2-ethylthiophene is 1: 0.95-1: 1.3, the reaction solvent is selected from toluene, and the ratio of the mass of the A6 to the volume of the toluene is 1: 5-1: 20;
preferably, in the step (4), the catalyst is selected from anhydrous aluminum chloride, the reaction temperature is 40-60 ℃, and the reaction time is 1.5-2.5 hours; the molar ratio of the A7 to the catalyst is 1: 0.005-1: 1.2, and the molar ratio of the A7 to the 1,1,3, 3-tetramethyldisiloxane is 1: 1-1: 5.5.
Preferably, in the step (5), the reaction temperature is-10 to-14 ℃, and the reaction time is 0.5 to 1.5 hours; the mass ratio of the A8 to the volume of the boron tribromide is 1: 1-1: 10, the reaction solvent is selected from dichloromethane, and the mass ratio of the A8 to the dichloromethane is 1: 5-1: 100;
preferably, in the step (6), the alkali is selected from sodium carbonate, the reaction temperature is 65-80 ℃, and the reaction time is 12-18 hours; the molar ratio of the A9 to the alkali is 1: 1-1: 30, the reaction solvent is selected from a mixed solvent of dioxane and water, the ratio of the mass of the A9 to the volume of the dioxane is 1: 3-1: 50, and the ratio of the mass of the A9 to the volume of the water is 1: 3-1: 50.
The unit of the mass to volume ratio is gram: and (4) milliliters.
The invention also provides application of the LH-1801 intermediate in preparing a compound LH-1801.
And the application of the compound A8 or the compound A9 in preparing (2-bromo-5-chloro-4- ((5-ethylthiophene-2-yl) methyl) phenyl) methanol.
Has the advantages that: the invention provides a brand-new LH-1801 intermediate and new compounds A8 and A9 for synthesizing the intermediate, and the LH-1801 synthesized by the intermediate can reduce the production risk and improve the product quality. In addition, the intermediate is synthesized by adopting a brand new intermediate compound and a synthesis route, so that the reaction risk is effectively reduced, the reaction type is simple, no dangerous reaction exists, the condition is mild, and the raw materials are easy to obtain.
Drawings
FIG. 1 is a drawing of Compound A41HNMR map.
FIG. 2 is a drawing of Compound A51HNMR map.
FIG. 3 is a drawing of Compound A81HNMR map.
FIG. 4 is a drawing of Compound A91HNMR map.
FIG. 5 is a drawing of Compound A101HNMR map.
Detailed Description
The present invention will be further described with reference to the following examples in order to provide a thorough understanding of the present invention.
EXAMPLE 1 Synthesis of LH-1801 intermediate (2-bromo-5-chloro-4- ((5-ethylthiophen-2-yl) methyl) phenyl) methanol, Compound A8 and Compound A9
The method comprises the following steps: synthesis of 5-bromo-2-chloro-4-methylbenzoic acid
Weighing liquid bromine (511g,3.2mol) into a 500mL three-necked bottle, cooling the ice bath to 5 ℃, weighing iron powder (48.6g,0.868mol) and adding the iron powder, keeping the temperature at 5 ℃, weighing A1 (2-chloro-4-methylbenzoic acid) (100g,0.586mol) and slowly adding the A1 (100g,0.586mol) in batches, wherein the heat release is obvious, keeping the temperature at less than or equal to 25 ℃, completing the addition, slowly removing the ice bath, reacting for two hours at 25 ℃, and completely reacting by TLC point plates. The target intermediate 5-bromo-2-chloro-4-methylbenzoic acid (142g,0.569mol yield: 97.6%)
MS+1:250
Step two: synthesis of methyl 5-bromo-2-chloro-4-methylbenzoate
A2 (5-bromo-2-chloro-4-methylbenzoic acid) (140g,0.561mol) crude product was weighed into a 2L three-necked flask, 1.5L of methanol was added thereto at 15 ℃, 129mL of concentrated sulfuric acid was slowly added thereto, the internal temperature was raised to 45 ℃, the mixture was heated to reflux, the external temperature was 70 ℃, the internal temperature was 65 ℃, and the reflux reaction was carried out for 12 hours. TLC spot plate reaction is complete. The final treatment was carried out by spin drying to obtain 135 g. Pure petroleum ether was passed through a column to obtain the target intermediate methyl 5-bromo-2-chloro-4-methylbenzoate (120g,0.455mol, yield: 81.2%)
MS+1：264
Step three: synthesis of 5-bromo-4- (bromomethyl) -2-chlorobenzoic acid methyl ester
Weighing A3 (5-bromo-2-chloro-4-methylbenzoic acid methyl ester) (88g,0.334mol) in A3L three-necked flask, adding 1.76L of carbon tetrachloride (molecular sieve drying) into the flask, stirring to dissolve the mixture, adding azobisisobutyronitrile (71.4g,0.4mol) into the flask at an internal temperature of 20 ℃, heating the mixture to 80 ℃ at an external temperature, refluxing the mixture at an internal temperature of 78 ℃, continuing to reflux the mixture for 28 hours, adding water to separate the mixture, spin-drying an organic phase, and separating and purifying the organic phase by a column (PE: EA is 100/0-300/1) to obtain a target intermediate A4 (5-bromo-4- (bromomethyl) -2-chlorobenzoic acid methyl ester) (42g,0.123mol, the yield: 36.7%)
MS+1：343
Step four: synthesis of 5-bromo-2-chloro-4- (methoxymethyl) benzoic acid
A4 (methyl 5-bromo-4- (bromomethyl) -2-chlorobenzoate) (40g,0.117mol) was weighed out into a 500mL three-necked flask, 200mL of methanol was added thereto and dissolved by stirring, sodium methoxide (25g,0.463mol) was added thereto at an internal temperature of 22 ℃ and heated to reflux, and the reaction was carried out at an internal temperature of 65 ℃ for 7 hours. Point TLC senses partial hydrolysis to acid, partial non-hydrolysis, post-treatment, adding appropriate amount of water, directly performing rotary evaporation concentration, and after two hours of concentration point TLC finds that all acid is available. After-treatment, the aqueous phase was removed by rotation, extracted with EA, separated, dried and the EA phase was removed by rotation to give the target intermediate 5-bromo-2-chloro-4- (methoxymethyl) benzoic acid (30g,0.107mol, yield: 92%)
MS+1:280
1HNMR(400MHz,DMSO):δ8.00(s,1H),7.56(s,1H),4.46(s,2H),3.41(s,3H).
Step five: synthesis of 5-bromo-2-chloro-4- (methoxymethyl) benzoyl chloride
A5 (5-bromo-2-chloro-4- (methoxymethyl) benzoic acid) (30g,0.107mol) was weighed out in a 500mL three-necked flask, 300mL of toluene was added thereto, DMF (0.36g,4.9mmol) was added thereto, internal temperature was 22 ℃, thionyl chloride (15.9g,0.133mol) was added thereto, and the mixture was heated in an oil bath to 65 ℃ for reaction for 7 hours. Then directly concentrated to dryness to give the desired intermediate 5-bromo-2-chloro-4- (methoxymethyl) benzoyl chloride (31.9g,0.107mol) which was used in the next reaction without any purification.
Step six: synthesis of (5-bromo-2-chloro-4- (methoxymethyl) phenyl) (5-ethylthiophen-2-yl) methanone
A6 (5-bromo-2-chloro-4- (methoxymethyl) benzoyl chloride) (31.9g,0.107mol) was weighed into a 1L three-necked flask, 270mL of toluene was added, then (12.1g,0.107mol) of 2-ethylthiophene was added, then the reaction solution was cooled to 10 ℃, and (14.4g,0.107mol) of anhydrous aluminum chloride was added thereto, and the reaction was heated to 50 ℃ for 2 hours. After the disappearance of the starting material was judged by TLC, the stirring was stopped and the target intermediate (5-bromo-2-chloro-4- (methoxymethyl) phenyl) (5-ethylthiophen-2-yl) methanone obtained was used directly in the next reaction without any post-treatment.
Step seven: synthesis of 2- (5-bromo-2-chloro-4- (methoxymethyl) benzyl) -5-ethylthiophene
The reaction solution of A7 (5-bromo-2-chloro-4- (methoxymethyl) phenyl) (5-ethylthiophen-2-yl) methanone in the previous step was cooled to about 10 ℃, and (13.5g,0.101mol) of anhydrous aluminum trichloride was added thereto, and (34.2g,0.255mol) of 1,1,3, 3-tetramethyldisiloxane was slowly added thereto, and the temperature was raised to 50 ℃ after the addition for reaction for 2 hours. The TLC starting material was completely reacted and two new spots were formed, and the target intermediate 2- (5-bromo-2-chloro-4- (methoxymethyl) benzyl) -5-ethylthiophene (13g,0.036mol yield: 34%) was obtained by passing through the column.
MS+1:360
1H NMR(400MHz,CDCl3):δ7.50(s,1H),7.43(s,1H),6.63(ddd,J＝4.3,3.4,2.2Hz,2H),4.47(s,2H),4.17(s,2H),3.49(s,3H),2.81(q,J＝7.5Hz,2H),1.30(t,J＝7.5Hz,3H).
Step eight: synthesis of 2- (5-bromo-4- (bromomethyl) -2-chlorobenzyl) -5-ethylthiophene
A8(2- (5-bromo-2-chloro-4- (methoxymethyl) benzyl) -5-ethylthiophene) (13g,0.036mol) was weighed into a 1L three-necked flask, 500mL of DCM was added thereto, cold hydrazine was cooled to-20 deg.C, 54.7mL of 1M boron tribromide in DCM was slowly added thereto, the temperature was controlled to be lower than-12 deg.C during the dropwise addition, and then the reaction was carried out at-12 deg.C for 1 hour with TLC monitoring to show completion of the starting material reaction. Quenching with ice water, separating, drying, spin-drying, and purifying by column chromatography to obtain the target intermediate 2- (5-bromo-4- (bromomethyl) -2-chlorobenzyl) -5-ethylthiophene (12g,0.029mol yield: 81.6%).
MS-1:407
1H NMR(400MHz,CDCl3):δ7.49(s,1H),7.46(s,1H),6.66(d,J＝3.4Hz,1H),6.64(d,J＝3.4Hz,1H),4.54(s,2H),4.17(s,2H),2.81(q,J＝7.5Hz,2H),1.30(d,J＝7.6Hz,3H).
Step nine: synthesis of (2-bromo-5-chloro-4- ((5-ethylthiophen-2-yl) methyl) phenyl) methanol
A9(2- (5-bromo-4- (bromomethyl) -2-chlorobenzyl) -5-ethylthiophene) (12g,0.029mol)) was weighed into a 500ml flask, 200ml dioxane, 200ml water, (17.8g,0.168mol) sodium carbonate was added thereto, the reaction was heated to 73 ℃ and reacted for 15 hours after TLC was essentially complete, post-treatment: spin-drying dioxane, extracting EA, drying EA to obtain 7.5 g of a crude product; then recrystallized from 75ml (PE/EA. RTM. 10/1) to give the final desired product (2-bromo-5-chloro-4- ((5-ethylthiophen-2-yl) methyl) phenyl) methanol (3.1g, 8.97mmol, purity: 99%, yield: 31%)
MS+1:346
1H NMR(400MHz,DMSO):δ7.61(s,1H),7.52(s,1H),6.70(d,J＝3.4Hz,1H),6.64(d,J＝3.4Hz,1H),5.57(t,J＝5.7Hz,1H),4.47(d,J＝5.6Hz,2H),4.16(s,2H),2.72(q,J＝7.5Hz,2H),1.18(t,J＝7.5Hz,3H).。
Claims (10)
1. An LH-1801 intermediate, wherein said intermediate is (2-bromo-5-chloro-4- ((5-ethylthiophen-2-yl) methyl) phenyl) methanol, and the structural formula is as follows:
2. a compound useful for preparing the LH-1801 intermediate of claim 1, wherein said compound is 2- (5-bromo-2-chloro-4- (methoxymethyl) benzyl) -5-ethylthiophene, having the formula A8:
3. a compound useful for preparing the LH-1801 intermediate of claim 1, wherein said compound is 2- (5-bromo-4- (bromomethyl) -2-chlorobenzyl) -5-ethylthiophene, having the formula a 9:
4. a process for the preparation of an intermediate LH-1801 as defined in claim 1, a compound as defined in claim 2 or a compound as defined in claim 3, which comprises the steps of:
(1) reacting the compound A4 with sodium methoxide under heating to obtain a compound A5;
(2) reacting the compound A5 with thionyl chloride to obtain a compound A6;
(3) reacting the compound A6 with 2-ethyl thiophene under the condition of a catalyst to obtain a reaction solution containing a compound A7;
(4) adding a catalyst and 1,1,3, 3-tetramethyldisiloxane into a reaction solution containing a compound A7, and heating for reaction to obtain a compound A8;
(5) reacting the compound A8 with boron tribromide to obtain a compound A9;
(6) and heating the compound A9 under the alkali condition for reaction to obtain a final target product compound A10.
5. The method according to claim 4, wherein in step (1), Compound A4 is prepared mainly by:
(1) reacting the compound A1 with bromine under the condition of a catalyst to obtain a compound A2;
(2) reacting the compound A2 with methanol under heating to obtain a compound A3;
(3) and heating and reacting the compound A3 with azodiisobutyronitrile and N-bromosuccinimide to obtain a compound A4.
6. The process for preparing an intermediate of LH-1801 as claimed in claim 4, wherein in step (1), the reaction temperature is 55-75 ℃ and the reaction time is 6-8 hours; the molar ratio of the A4 to the sodium methoxide is 1: 1.5-1: 5; in the step (2), the reaction temperature is 55-75 ℃, and the reaction time is 6-8 hours; the molar ratio of the A5 to the thionyl chloride is 1: 1-1: 4.
7. The process for preparing LH-1801 intermediate as claimed in claim 2, wherein in step (3), the catalyst is selected from anhydrous aluminum chloride, the reaction temperature is 40-60 ℃ and the reaction time is 1.5-2.5 hours; the molar ratio of the A6 to the catalyst is 1: 1-1: 2.5, and the molar ratio of the A6 to the 2-ethylthiophene is 1: 0.95-1: 1.3; in the step (4), the catalyst is selected from anhydrous aluminum chloride, the reaction temperature is 40-60 ℃, and the reaction time is 1.5-2.5 hours; the molar ratio of the A7 to the catalyst is 1: 0.005-1: 1.2, and the molar ratio of the A7 to the 1,1,3, 3-tetramethyldisiloxane is 1: 1-1: 5.5.
8. The process for preparing an intermediate of LH-1801 as claimed in claim 2, wherein in step (5), the reaction temperature is from-10 ℃ to-14 ℃ and the reaction time is from 0.5 to 1.5 hours; the mass ratio of the A8 to the volume of the boron tribromide is 1: 1-1: 10; in the step (6), the alkali is selected from sodium carbonate, the reaction temperature is 65-80 ℃, and the reaction time is 12-18 hours; the molar ratio of the A9 to the alkali is 1: 1-1: 30.
9. Use of an intermediate as claimed in claim 1 for the preparation of the compound LH-1801.
10. Use of a compound according to claim 2 or a compound according to claim 3 for the preparation of (2-bromo-5-chloro-4- ((5-ethylthiophen-2-yl) methyl) phenyl) methanol.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115819398A (en) * | 2022-10-31 | 2023-03-21 | 江苏联环药业股份有限公司 | SGLT2 inhibitor key intermediate and preparation method and application thereof |
| CN119143719A (en) * | 2024-09-12 | 2024-12-17 | 扬州市普林斯医药科技有限公司 | Preparation method of LH-1801 key intermediate |
Citations (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1543467A (en) * | 2001-08-16 | 2004-11-03 | Diazacycloalkanes as oxytocin agonists | |
| CN101495495A (en) * | 2006-07-27 | 2009-07-29 | 中外制药株式会社 | Substituted spiroketal derivative and use thereof as therapeutic agent for diabetes |
| CN101998962A (en) * | 2008-02-13 | 2011-03-30 | 赛诺菲-安万特 | Novel aromatic fluoroglycoside derivatives, medicines comprising said compounds and uses thereof |
| CN102264714A (en) * | 2008-10-17 | 2011-11-30 | 詹森药业有限公司 | Process for the preparation of compounds useful as inhibitors of sglt |
| CN103570671A (en) * | 2012-09-26 | 2014-02-12 | 上海天慈生物谷生物工程有限公司 | Efficient blood glucose reducing compound as well as preparation and application thereof |
| CN103819465A (en) * | 2003-08-01 | 2014-05-28 | 田边三菱制药株式会社 | Novel compound |
| CN103910702A (en) * | 2008-08-22 | 2014-07-09 | 泰拉科斯有限公司 | Processes For The Preparation Of Sglt2 Inhibitors |
| CN104086523A (en) * | 2014-06-09 | 2014-10-08 | 上海方楠生物科技有限公司 | Method for preparing canagliflozin intermediate 2-(4-fluorophenyl)-5-[(5-halogen-2-methylphenyl)methyl]thiophene |
| CN104744449A (en) * | 2015-03-21 | 2015-07-01 | 北京工业大学 | Preparation method of canagliflozin hemihydrate and monocrystal thereof |
| CN104926803A (en) * | 2015-06-17 | 2015-09-23 | 南通常佑药业科技有限公司 | Preparation method for novel SGLT2 inhibitor medicine |
| CN105272960A (en) * | 2014-07-18 | 2016-01-27 | 上海科胜药物研发有限公司 | Preparation method of canagliflozin intermediate 2-(2-methyl-5-bromobenzyl)-5-(4-fluorobenzene)thiophene |
| WO2016083790A1 (en) * | 2014-11-25 | 2016-06-02 | Cipla Limited | Process for the preparation of canagliflozin |
| CN106317068A (en) * | 2015-06-23 | 2017-01-11 | 中国科学院上海药物研究所 | C, O-spiro aryl glycoside compound and preparation and application thereof |
| CN107556287A (en) * | 2017-09-01 | 2018-01-09 | 连云港恒运药业有限公司 | Canagliflozin intermediate synthetic method |
| CN108069997A (en) * | 2016-11-08 | 2018-05-25 | 北京藏卫信康医药研发有限公司 | A kind of tofogliflozin intermediate and preparation method thereof |
| CN108892659A (en) * | 2018-08-07 | 2018-11-27 | 浙江华海致诚药业有限公司 | A kind of canagliflozin impurity and preparation method thereof |
-
2021
- 2021-06-28 CN CN202110721400.1A patent/CN113429379A/en not_active Withdrawn
Patent Citations (17)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1543467A (en) * | 2001-08-16 | 2004-11-03 | Diazacycloalkanes as oxytocin agonists | |
| CN103819465A (en) * | 2003-08-01 | 2014-05-28 | 田边三菱制药株式会社 | Novel compound |
| CN101495495A (en) * | 2006-07-27 | 2009-07-29 | 中外制药株式会社 | Substituted spiroketal derivative and use thereof as therapeutic agent for diabetes |
| CN101998962A (en) * | 2008-02-13 | 2011-03-30 | 赛诺菲-安万特 | Novel aromatic fluoroglycoside derivatives, medicines comprising said compounds and uses thereof |
| CN103910702A (en) * | 2008-08-22 | 2014-07-09 | 泰拉科斯有限公司 | Processes For The Preparation Of Sglt2 Inhibitors |
| CN102264714A (en) * | 2008-10-17 | 2011-11-30 | 詹森药业有限公司 | Process for the preparation of compounds useful as inhibitors of sglt |
| CN103570671A (en) * | 2012-09-26 | 2014-02-12 | 上海天慈生物谷生物工程有限公司 | Efficient blood glucose reducing compound as well as preparation and application thereof |
| CN104086523A (en) * | 2014-06-09 | 2014-10-08 | 上海方楠生物科技有限公司 | Method for preparing canagliflozin intermediate 2-(4-fluorophenyl)-5-[(5-halogen-2-methylphenyl)methyl]thiophene |
| CN105272960A (en) * | 2014-07-18 | 2016-01-27 | 上海科胜药物研发有限公司 | Preparation method of canagliflozin intermediate 2-(2-methyl-5-bromobenzyl)-5-(4-fluorobenzene)thiophene |
| WO2016083790A1 (en) * | 2014-11-25 | 2016-06-02 | Cipla Limited | Process for the preparation of canagliflozin |
| CN104744449A (en) * | 2015-03-21 | 2015-07-01 | 北京工业大学 | Preparation method of canagliflozin hemihydrate and monocrystal thereof |
| CN104926803A (en) * | 2015-06-17 | 2015-09-23 | 南通常佑药业科技有限公司 | Preparation method for novel SGLT2 inhibitor medicine |
| CN106317068A (en) * | 2015-06-23 | 2017-01-11 | 中国科学院上海药物研究所 | C, O-spiro aryl glycoside compound and preparation and application thereof |
| CN107709332A (en) * | 2015-06-23 | 2018-02-16 | 中国科学院上海药物研究所 | A kind of C, O loop coil aryl glycoside class compound and its preparation and application |
| CN108069997A (en) * | 2016-11-08 | 2018-05-25 | 北京藏卫信康医药研发有限公司 | A kind of tofogliflozin intermediate and preparation method thereof |
| CN107556287A (en) * | 2017-09-01 | 2018-01-09 | 连云港恒运药业有限公司 | Canagliflozin intermediate synthetic method |
| CN108892659A (en) * | 2018-08-07 | 2018-11-27 | 浙江华海致诚药业有限公司 | A kind of canagliflozin impurity and preparation method thereof |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115819398A (en) * | 2022-10-31 | 2023-03-21 | 江苏联环药业股份有限公司 | SGLT2 inhibitor key intermediate and preparation method and application thereof |
| CN115819398B (en) * | 2022-10-31 | 2024-06-14 | 江苏联环药业股份有限公司 | Key intermediate of SGLT2 inhibitor, and preparation method and application thereof |
| CN119143719A (en) * | 2024-09-12 | 2024-12-17 | 扬州市普林斯医药科技有限公司 | Preparation method of LH-1801 key intermediate |
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